Test method and test drive for analysing a body fluid

ABSTRACT

There is provided a test method for analysing a body fluid in which a test tape is used in a test device to successively provide analytical test fields stored on the test tape, wherein body fluid is applied by a user to the test field provided at a time and the said test field is photometrically scanned using a measuring unit of the device to record measurement signals. To increase the measurement reliability, it is proposed that a control value is determined from a time-dependent and/or wavelength-dependent change in the measurement signals and that the measurement signals are processed as valid or discarded as erroneous depending on the control value.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.15/235,154 (filed 12 Aug. 2016), which is a continuation of U.S. patentapplication Ser. No. 14/703,312 (filed 4 May 2015), which iscontinuation of U.S. patent application Ser. No. 13/209,708 (filed 15Aug. 2011; now U.S. Pat. No. 9,052,293, which issued 9 Jun. 2015), whichis a continuation of Intl Patent Application No. PCT/EP2010/052012(filed 18 Feb. 2010), which claims priority to and the benefit of EPPatent Application No. 09153113.7 (filed 18 Feb. 2009). Each patentapplication is incorporated herein by reference as if set forth in itsentirety.

TECHNICAL FIELD

This disclosure concerns a test method and device for analysing a bodyfluid for blood sugar determination in which a test tape preferably inthe form of a tape cassette is used in a test device to successivelyprovide a plurality of analytical test fields stored on the test tape bymeans of tape transport, where a body fluid is applied by a user to thetest field provided at a time and the test field is photometricallyscanned using a measuring unit of the device to record measurementsignals. This disclosure additionally concerns certain functions andfailsafes performed on dry and wetted analytical test fields as part ofan initiated test sequence.

BACKGROUND

A generic test tape device is, for example, known from the EP PatentApplication No. 08166955.8 of the applicant. It describes a tapecassette with a test tape on which positioning markers are located inaddition to the analytical test fields to ensure a reliable positioningin various functional positions for each relevant tape section.

A method of detecting erroneous positioning of a test strip that can beanalysed by optical means, which is based on comparing two measuredvalues from measurement spots spaced apart from one another in theinsertion direction of the test strip in a test device, is known from DE199 32 846 A1. However, the conditions in test strip systems are hardlycomparable with tape systems in so far as the test strips are insertedindividually into a device guide, whereas tape transport and tapeguidance is affected by the consumable itself.

What is needed therefore is to further improve the test methods anddevices proposed in the prior art and ensure an increased securityagainst operating errors and measuring errors.

BRIEF SUMMARY

A first aspect of the invention is based on the idea of deducing anerror analysis from an expected signal change of a measurement signalrelevant for the test result. Accordingly it is proposed that a controlvalue is determined from a time-dependent and/or wavelength-dependentchange of the measurement signals and that the measurement signals areprocessed as valid or discarded as erroneous depending on a presetthreshold value of the control value. In this manner, it is possible tosubstantially exclude falsifying external effects on the measurementresult. It is also possible to check several potential faults inparallel.

An error discrimination based on the circumstances of the sampleapplication provides that the measurement signals are recorded at twodifferent wavelengths and that the control value is determined from asignal difference of the measurement signals at different wavelengths,wherein a fault is detected by the device and optionally an error signalis triggered when the signal difference disappears. This also inparticular allows those manipulations to be detected in which a user forexample presses his finger against the test field without applying asample.

The signal difference of the measurement signals at differentwavelengths is advantageously based on the wetting of the provided testfield with the body fluid so that it is possible to reliably detecterrors even at low analyte concentrations. In this connection, it isadvantageous when the measurement signals at different wavelengths areobtained in the visible wavelength range and in the infrared range.

Another advantageous embodiment is that the control value is determinedfrom a signal difference of the measurement signals recorded at thebeginning and end of a measurement interval, wherein a fault is detectedwhen the signal difference disappears. This type of error recognition isbased on the special reaction kinetics of an analyte on test fields thatchange colour, which can thus be distinguished from a mechanical tapemanipulation.

According to a further advantageous embodiment, the measurement signalsare recorded over the duration of a measurement interval, and thecontrol value is determined from a change in the measurement signal inan initial period of the measurement interval and a fault is detectedwhen the change in measurement signal is below a preset minimum value.This also allows environmental effects to be excluded which, incomparison with a regular measurement, only result in a considerablyreduced initial signal change.

In the preparation phase for liquid application, it is advantageous whenblank values are recorded cyclically on the test field that is provided,and when the control value is determined from a change in the blankvalue compared to an initial blank value, where an application of liquidis determined when the change in blank value is above the thresholdvalue and a fault is determined when it is below the threshold value.

The current blank value is advantageously taken into consideration fordetermining a relative measurement value for an analyte in the bodyfluid in the case of a change in the blank value up to a preset limitvalue. This allows one to obtain a referenced measurement value withoutslight changes in the reference quantity resulting in a falsifiedresult.

The aforementioned advantages also result for a corresponding device forcarrying out the method according to the invention.

Another aspect of the invention is that a lot control value is stored ona storage medium assigned to the test tape, where a test field controlvalue is determined from a blank measurement of a yet unused first testfield, and where the usability of the first test field is determined bycomparing the lot control value and the test field control value. Such aquality check enables damaging effects on the test material, which isfor example only used as a consumable after a long period of storage, tobe detected. As a result of this check, it is also possible to rate theentire test tape as being unusable if the test field control value ofthe first test field on the test tape deviates by more than a specifiedtolerance from the lot control value.

The lot control value is advantageously determined during a batchwiseproduction of test tapes by measurement of test fields and calibrationfields on the test tape material. This can be reliably carried out whenproducing tests in a tape form due to the homogeneous processingprocesses.

To allow for a change that can be tolerated for subsequent measurements,it is advantageous when the test field control value of a test field ofthe test tape that has been provided and rated as usable is stored inthe device as a new tape control value, and when the test field controlvalue correspondingly determined of the next test field is compared withthe stored tape control value for a check of the usability of the nexttest field.

An advantageous measured value referencing can be achieved by carryingout a calibration measurement by detecting preferably a whitecalibration field associated with the respective test field by means ofthe measuring unit, and determining the test field control value as arelative value from the blank measurement and the calibrationmeasurement.

It is advantageous for a substantially automatic processing when the lotcontrol value is stored in a storage means, preferably in an RFID chip,applied to the tape cassette so that a comparison can be carried out bythe device without further user interaction.

Another aspect of the invention is also that a signal offset of themeasuring unit is recorded in a reference area of the test tapeassociated with the provided test field and that when the signal offsetexceeds a specified threshold value, an error indication is triggered.This allows contamination or other changes in the optical path to bereliably detected.

Another aspect provides that the signal offset is detected on a darkcoloured black field as a reference area of the test tape, where theblack field is arranged on a section of tape adjacent to the respectivetest field and is positioned by tape transport in the detection area ofthe measuring unit.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is further elucidated in the following on the basis of theexemplary embodiment shown in the drawings.

FIG. 1 shows an analytical test tape system for blood sugardetermination comprising a hand-held device and a test tape cassette ina cut open perspective view.

FIG. 2 shows an enlargement of a section of FIG. 1 in the area of ameasuring tip.

FIG. 3 shows a test tape section in a top view.

FIG. 4 shows a measured value diagram in various phases of themeasurement process.

FIG. 5 shows a measured value diagram as a function of the concentrationof an analyte for two different wavelengths.

DETAILED DESCRIPTION

The test tape system shown in FIG. 1 enables the use of a tape cassette12 with a test tape 14 that can be wound forwards as a consumable in ahand-held device 10 for carrying out glucose tests, where functionchecks are carried out in various phases of the measurement process. Thegeneral principle of the device is described in EP Patent ApplicationNo. 02026242.4, which is incorporated herein by reference.

The hand-held device 10 has a tape drive (motor 15 with drive spindle16), a measuring unit 18, a microprocessor-assisted control device 20and an energy supply 22. A display that is not shown enables the outputof measurement results and device messages for the user.

The tape cassette 12 that can be inserted into a receiving compartment23 of the device 10 comprises a supply spool 24 for unused test tape 14and a take-up spool 26 for used test tape that can be coupled to thedrive 16 as well as a tape guide 25 with a deflecting tip 34. The supplyspool 24 is arranged in a storage chamber 28 that is sealed against theenvironment.

The test tape 14 is provided in sections with test fields 32 that arethus arranged in a given sequence in the direction of tape transport. Inthis connection, it should be taken into consideration that the testfields 32 contaminated with blood are disposed of on the take-up spool26 and hence it is not feasible to rewind the tape.

The front side of the test field 32 that is provided or active in eachcase can be loaded with sample liquid, in particular blood or tissuefluid, in the area of the deflecting tip 34, which is accessible fromoutside. The analyte (glucose) is detected by a reflection-photometricdetection of a colour change of the test fields 32 from the rear side bymeans of the measuring unit 18. For this purpose, the test fields 32 areapplied to a transparent carrier foil as a dry reagent layer. The testfields 32 can be successively brought into use by appropriatelyadvancing the tape. In this manner, it is possible to carry out multipletests for patient self-monitoring without having to frequently replacethe consumables.

As shown in FIG. 2, the measuring unit 18, fixed permanently in thedevice and engaging in the cassette 12, has three light-emitting diodes36, 38, 40 as a radiation source and a photodiode 41 as a detector for areflection-photometric signal detection. An optical system 43 provides afocused optical path with imaging of light spots of defined size andintensity on the rear side of the tape. The middle light-emitting diode38 radiates in the visible (red) wavelength range at about 650 nm,whereas the outer light-emitting diodes 36, 40 work in the infraredrange at 875 nm. The light scattered backwards on the test strip 48 isdetected at a specified time interval using the photodiode 41.

As shown in FIG. 3, spaced apart test fields 32 are each locatedindividually on an allocated tape section 42, which is additionallyprovided with further check or control fields in the form of a blackfield 44 and a white field 46. The test field 32 has a central teststrip 48 formed by the test chemistry layer, which is laterallydelimited by two hydrophobic edge strips 50. The sample liquid appliedto the front side of the test field 32 wets the test strip 48 in theform of a sample spot 52, which is scanned from the transparent rearside of the tape by the light spots 36′, 38′, 40′ of the light-emittingdiodes 36, 38, 40 in the measuring position on the deflecting tip 34.However, since the tape can be transported only in one direction (arrow54) the check fields 44, 46 are firstly detected before the actualmeasurement as elucidated in more detail in the following.

The white field 46 of the yet unused tape section 42 is located on thedeflection tip 34 in front of the measuring unit 18 in the stand-byposition. The white field 46 printed onto the carrier tape 34 in whitepaint is of such a size that the measuring window detected by themeasuring unit 18 is completely covered. It is also possible to positionan upstream black field 44 for measurement before taking up the stand-byposition.

As shown in FIG. 4, the measurement cycle for each tape section 42 isdivided into various phases. In phase Ia, the black field 44 is scannedto detect contamination and optionally for self correction by the deviceas will be elucidated in more detail in the following. In phase Ib, thewhite field 46 is measured to check tape quality and optionally for selfcorrection. In phase Ic, a so-called dry blank value DBV is determinedon the yet unused test field 32. Then, the user is prompted to applyblood (Id). This ends the preparation phase.

In phase II, a wetting detection is carried out on the test field 32 bymeans of the IR light-emitting diodes 36, 40. The signal intensitydecreases when the test strip 48 is wetted.

Subsequently, the kinetics of the analyte-specific measurement signal ismonitored on the bases of the colour change of the test strip 48 inphases III and IV at a measurement interval of for example 0.2 s. Theend phase IIIb of the monitoring of the kinetics is reached when thediminishing signal change that depends on the chemical reaction ratereaches a termination threshold. Then, a duplicate measurement takesplace using LED 38 in phase IV to determine an averaged end value EV.The glucose concentration is then determined in relative remission bycalculating a quotient from this end value EV and the dry blank valueDBV (in general the relative remission is calculated from the ratio ofthe actual measured value to the dry blank value). In addition, in phaseV, a homogeneity measurement of the sample spot 52 is provided to detectunderdosing, which is based on a quantitative signal comparison of thetwo IR-LEDs 36, 40. Finally, the glucose concentration is shown to theuser in the display of the device 10.

Apart from the actual measurement for determining the glucoseconcentration, the functions or fail safes mentioned above are put intopractice as follows:

The contamination detection takes place using LED 38 after inserting thecassette 12 and following each glucose measurement by measuring thesignal offset on the black field 44. This offset is generated by theentire measurement environment with the LEDs switched on withoutinvolvement of a test. It is thus an additive quantity when determiningthe measured value. The emitted light is partially reflected and passedto the detector 41 as a result of contamination or other optical changesin the optical path for example due to foreign bodies, dust andscratches. In the offset detection, the black field 44 serves as asubstitute for a black hollow space which does not reflect any light.Basically it would, however, also be possible to carry out a measurementthrough the transparent carrier tape into the dark interior space of thedevice.

The detected signal offset is compared with the threshold value storedin the device 10, which was determined during the product manufacture asa lot mean. If the deposited threshold value is exceeded, then an errormessage is triggered.

To check the quality of the tape cassette 12 used possibly after a longstorage period as a disposable article, a reference value WF is recordedat least on the first white field 46 on the test tape 14. Subsequently,potential damage to the test strip chemistry for example due toenvironmental effects is detected by a corresponding change of the dryblank value DBV of the first test field 32. For this purpose, theabsolute remission value is not used but rather the relative remissionvalue based on the reference value WF.

A corresponding lot control value CC is determined during a batchwiseproduction of test tapes 14 by measuring test fields 32 and white fields46 on the test tape material. The tape is manufactured in a roll-to-rollprocess that allows such a control value assignment to a substantiallyuniform coating. The lot control value is stored in an RFID chip 56 onthe cassette 12 and read out and processed by the device electronics 20.The RFID chip 56 is attached to the outside of the cassette 12 and isonly shown symbolically in the cut open diagram of FIG. 2.

The test field quality check is negative when the following condition isfulfilled:DBV₁/WF₁ <CC−ΔC  (1),in which ΔC is a tolerance value and the index 1 refers to the firsttape section 42. In this case, a corresponding error message is issued,and the cassette 12 is discarded if necessary.

If the result is positive, it is also possible to carry out a qualitycheck for subsequent tests within narrow limits. For this purpose, therelative remission value C_(n-1) of the currently used test field isstored in a device memory and used instead of the lot control value CCin accordance with the above-mentioned equation (1). Hence, a subsequentquality check of a next test field n is negative when:DBV_(n)/WF_(n) <C _(n-1) −ΔC  (2).

In general, a calibration of the devices 10 by the manufacturer ensuresthat relevant measured values can only be generated in the specifiedmeasuring range of all opto-electronic components. In this case, theelectrical parameters of the three LEDs 36, 38, 40 and the opticalparameters are calibrated.

A self-correction process or a calibration by the device is in principlealso possible to minimize the specific effect of the signal offset andvarying absolute measurements on the measured value determination. Theoptical offset varies from cassette to cassette for manufacturingreasons. In addition, a spacing component subject to tolerances occursdue to the separation of the instrument optical system and tape guidanceby the cassette.

The black and white fields 44, 46, which are located on the test tape 14in front of each test field 32, are in turn used for the referencemeasurement. These fields are already measured during the manufactureand provided with a lot mean value. These values are then stored on theRFID chip 56 as a reference value.

The black field value measured on the first black field 44 afterinserting a cassette 12 is checked to see whether it is near to themanufacturer's lot mean value for the optical offset within a specifiedtolerance. If this is the case, the lot mean value is retained. If themeasured black field value deviates from this tolerance range, thedifference to the lot mean value is determined and added to the opticaloffset. The optical offset is subtracted from the gross measurementsignals obtained subsequently on the test fields 32.

However, the correction of the optical offset is only carried out up toa defined limit. When this limit is exceeded, an error message istriggered as described above. The black field measurement is used beforeeach subsequent test only to detect contamination.

In the case of the white field calibration, the individual sensitivityvalue of the cassette is determined by comparing the measured valuerecorded on the white field 46 with the lot mean value stored on theRFID chip 56 as an absolute remission. If the measured white field valuem_(K) is near to the lot mean value m_(W) within a tolerance range, thenthe lot mean value m_(W) is used for a subsequent scaling of theoffset-corrected gross measurement signal and otherwise the individualcassette sensitivity m_(K) is used. However, an error message is sentout when a threshold value for deviation is exceeded.

To substantially exclude an unintentional generation of a measured valuedue to operating errors, it is possible to determine a control valuefrom a time-dependent and/or wavelength-dependent change in themeasurement signals, in which case the measurement signals can then befurther processed as valid or be rejected as erroneous depending on athreshold value of the control value.

A first such fault can be that due to the distance-dependency of themeasuring principle an artificial measuring result could be generated bypressing against the deflecting tip 34 without a sample having beenapplied. To exclude this, measurement signals are recorded on the testfield 32 at two different wavelengths, and the control value isdetermined from a difference in the signals of the measurement signalsat different wavelengths.

As shown in FIG. 5, when a sample is measured using differentwavelengths, this results in different values for the relative remissionover the entire range of the analyte or glucose concentration to beanalyzed. This difference in signals arises due to the wetting of thetest field 32 with the body fluid (hence a difference is found even at asample concentration of zero) and strengthens when the test chemistrysystem forms an intensified reaction colour. If a measurement signal canbe generated only by pressing, the typical difference in the LEDs 38, 40at different wavelengths cannot be observed due to the absence ofwetting and the absence of reaction colour by which means a fault isdetected. The specified threshold value of the signal difference can forexample be at 3% relative remission.

Another scenario for an unintentional generation of measured values isthat an erroneous detection of an application of blood is provoked by ashift in the tape. If a dark edge strip 50 of the test field 32 isshifted into the optical path of the measuring unit 18 by a usermanipulation, high measured values can be generated without a samplehaving been applied.

Typical reaction kinetics of blood samples on a test field 32, however,exhibit a signal amplitude of about 10% above about 100 mg/dl glucoseconcentration as determined as the difference between the first and lastkinetic measurement in phase III (FIG. 4). If, in contrast, the testtape is merely shifted in phase II as described above, there is anabrupt darkening and afterwards a constant signal i.e. variable reactionkinetics and an appreciable signal amplitude are not observed in phaseIII. Thus, an error can be detected by determining the control valuefrom a signal difference of signals measured at the beginning and end ofa measurement interval and detecting a fault when the signal differenceis almost zero.

If a test field 32 is located in front of the optical system 43 in thestate of sample application detection (phase II in FIG. 4), the controldevice 20 of the instrument 10 interprets a change in signal by aspecified amount as a sample application and starts the analysis. Highair humidity, as well as exposure to sunlight, could already lead tosuch a signal change without sample application under unfavourablecircumstances and thus result in a start of the measurement.

To prevent this, the time course of the change in blank signal ischecked in the state of awaiting the sample. Whereas application of ablood sample already leads to a decrease in remission of several percentwithin half a second, such a decrease is only achieved over a period ofmore than 20 seconds upon exposure to sunlight or air humidity.Consequently, it is possible that periodic blank values are recordedperiodically on the test field provided for the sample application andthat the control value is determined from a change in the blank valuecompared to an initial blank value where an application of liquid isdetected when the change in the blank value is above a predeterminedthreshold value (of for example about 5%) and a fault is detected whenit is below this value if necessary after a specified waiting time.

Another measurement problem can be that the dry blank value of a testfield 32 that is provided but is still unused, is for example changed bythe effect of light or moisture, and thus results in a falsificationwhen used as a reference value for the determination of the relativeremission. The measured value of the unused test field can therefore bechecked periodically in the state of awaiting a sample and either beupdated to prevent falsifications of the measured value or to abort themeasurement with an error message above a certain limit value of forexample more than 0.5%/s relative remission change.

Although embodiments of the invention have been described using specificterms, such description is for illustrative purposes only, and it is tobe understood that changes and variations obvious to the skilled artisanare to be considered within the scope of the claims that follow andtheir equivalents.

The invention claimed is:
 1. A method of detecting a test field shiftingerror resulting from unintentional user manipulation of a test tapehaving a plurality of test fields each applied to the test tape as a dryreagent layer, the method comprising the steps of: applying a body fluidsample to an unused test field of the test tape, said applying beingeffective to initiate a test having an analyte measurement intervalcomprising a duration including a beginning and an end, wherein the testtape is in a test device having a measuring unit comprising at least oneradiation source to generate at least one wavelength of light and aphotodiode for reflection-photometric signal detection of the at leastone wavelength of light; using the measuring unit, photometricallyscanning the test field having a body fluid sample applied and detectingrelative remission measurement signals of the at least one wavelength oflight generated by the at least one radiation source over the durationof the analyte measurement interval; calculating a control value basedupon a measurement signal difference between a relative remissionmeasurement signal detected at the beginning of the analyte measurementinterval and a relative remission measurement signal detected at the endof the analyte measurement interval; and detecting a test field shiftingerror and discarding the test if the control value is about zero whereinthe error is based on an expectation of a time-dependent change inrelative remission measurement signals from the beginning to the end ofthe analyte measurement interval when a test field is not improperlymanipulated during the analyte measurement interval.
 2. The method ofclaim 1, wherein the test tape further includes dark edge strips locatedadjacent to at least two sides of each of the plurality of test fields.3. A device for analyzing an analyte in a body fluid sample, the devicecomprising: a measuring unit having at least one radiation source togenerate at least one wavelength of light; a photodiode forreflection-photometric signal detection of the at least one wavelengthof light; a test tape having a plurality of analytical test fields eachapplied to the test tape as a dry reagent layer and each in a dedicatedsection of the test tape, wherein the analytical test fields can besuccessively provided for application of the body fluid sample by meansof tape transport and can be scanned using the measuring unit to detectrelative remission measurement signals from the at least one wavelengthover a duration of a measurement interval; and a controller configuredto carry out one or more function checks, one said function checkcomprising a check for a test field shifting error resulting fromunintentional user manipulation of a test tape, performed by applying abody fluid sample to an unused test field of the test tape to initiate atest having an analyte measurement interval comprising a durationincluding a beginning and an end, photometrically scanning the testfield having the body fluid sample applied using the measuring unit anddetecting relative remission measurement signals of the at least onewavelength of light generated by the at least one radiation source overa duration of the analyte measurement interval, calculating a controlvalue based upon a measurement signal difference between a relativeremission measurement signal detected at the beginning of the analytemeasurement interval and a relative remission measurement signaldetected at the end of the analyte measurement interval, and detecting atest field shifting error and discarding the test if the control valueis about zero, wherein the error is based on an expectation of atime-dependent change in relative remission measurement signals from thebeginning to the end of the analyte measurement interval when a testfield is not improperly manipulated during the analyte measurementinterval.
 4. A device for analyzing an analyte in a body fluid sample,the device comprising: a measuring unit having at least one radiationsource to generate at least one wavelength of light; a photodiode forreflection-photometric signal detection of the at least one wavelengthof light; a test tape having a plurality of analytical test fields eachapplied to the test tape as a dry reagent layer and each in a dedicatedsection of the test tape, wherein the analytical test fields can besuccessively presented for application of the body fluid sample by meansof tape transport and can be scanned using the measuring unit to detectrelative remission measurement signals from the at least one wavelengthover a duration of a measurement interval; and a controller configuredto carry out one or more function checks, one said function checkcomprising detecting reagent layer failure, performed by presenting anunused one of said analytical test fields to initiate a test having awaiting time comprising a duration including a beginning and an end,photometrically scanning the unused one of said analytical test fieldswith the measuring unit and detecting relative remission measurementsignals of the at least one wavelength of light generated by the atleast one radiation source over the duration of the waiting time priorto applying a body fluid sample to the unused one of said analyticaltest fields, calculating a control value based upon a blank measurementsignal difference between relative remissions detected at the beginningand at the end of the waiting time, and detecting a reagent layerfailure and discarding the test if the control value is above zero andbelow a preset threshold.